Novel selective a2c agonists have been discovered by the introduction of a heteroaryl group at the 6-position of the central core (phenylmorpholine and indoline). Compounds active in vitro and in vivo have been identified in both the neuropathic pain and the decongestion models. Selected biaryl agonists exhibit an improved pharmacokinetic profile and in vivo efficacy in several neuropathic pain models compared to compounds with N-substituted central cores. The main issue in this series of compounds have been CYP450 inhibition and 1A1 enzyme induction in the rat. However, this liabilities has been overcome by selecting the right heterocycle-central core combination and by the introduction of ortho-substituents (alkyl and amino groups) on the heterocycle at the 6-position.

Biaryl indolines and phenylmorpholines as potent and selective α2c adrenoreceptor agonists

244th National Meeting (2012)

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